Matrix metalloproteinase-3 causes dopaminergic neuronal death through Nox1-regenerated oxidative stress.
Matrix metalloproteinase-3 causes dopaminergic neuronal death through Nox1-regenerated oxidative stress.
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DOI：
10.1371/journal.pone.0115954
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kim YS
中科院分区：
文献类型：
--
作者：
Choi DH;Kim JH;Seo JH;Lee J;Choi WS;Kim YS
本研究探讨了基质金属蛋白酶3(MMP3)和NADPH氧化酶1(Nox1)在多巴胺(DA)神经元死亡过程中的相互作用。我们发现，在6-OHDA暴露的大鼠DA神经元n27细胞中，MMP3的激活通过线粒体活性氧(ROS)的产生和随后的rac1的激活导致Nox1的诱导，最终导致Nox1衍生的超氧化物的产生。而MMP3抑制剂NNGH可显著抑制线粒体ROS及随后的Nox1诱导，而可能的Nox抑制剂apocynin和Nox1选择性抑制剂GKT137831均不能降低6-OHDA诱导的线粒体ROS。然而，MMP3和Nox1的两种抑制剂都类似地减弱了6-OHDA诱导的n27细胞死亡。RNAi介导的对MMP3或Nox1的选择性抑制表明，MMP3或Nox1的敲除显著减少了6-OHDA诱导的n27细胞ROS的产生。6-OHDA诱导的Nox1可被MMP3基因敲除，而Nox1基因敲除并不改变MMP3的表达。在n27细胞或大鼠黑质(SN)中直接过表达自激活的MMP3(ActMMP3)会增加Nox1的表达。通过腺相关病毒介导的Nox1特异性shRNA的过表达，选择性地敲除黑质中的Nox1，大大减轻了actMMP3介导的多巴胺能神经元的丢失。此外，经N-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)处理的Mmp3基因缺失小鼠的Nox1表达显著降低。我们共同建立了氧化应激介导的多巴胺能神经元死亡的新的分子机制，其中MMP3激活是导致线粒体ROS、Nox1诱导和最终多巴胺能神经元死亡的关键上游事件。我们的发现可能会导致新的治疗方法的发展。
In the present study we investigated the interplay between matrix metalloproteinase 3 (MMP3) and NADPH oxidase 1 (Nox1) in the process of dopamine (DA) neuronal death. We found that MMP3 activation causes the induction of Nox1 via mitochondrial reactive oxygen species (ROS) production and subsequently Rac1 activation, eventually leading to Nox1-derived superoxide generation in a rat DA neuronal N27 cells exposed to 6-OHDA. While a MMP3 inhibitor, NNGH, largely attenuated mitochondrial ROS and subsequent Nox1 induction, both apocynin, a putative Nox inhibitor and GKT137831, a Nox1 selective inhibitor failed to reduce 6-OHDA-induced mitochondrial ROS. However, both inhibitors for MMP3 and Nox1 similarly attenuated 6-OHDA-induced N27 cell death. RNAi-mediated selective inhibition of MMP3 or Nox1 showed that knockdown of either MMP3 or Nox1 significantly reduced 6-OHDA-induced ROS generation in N27 cells. While 6-OHDA-induced Nox1 was abolished by MMP3 knockdown, Nox1 knockdown did not alter MMP3 expression. Direct overexpression of autoactivated MMP3 (actMMP3) in N27 cells or in rat substantia nigra (SN) increased expression of Nox1. Selective knockdown of Nox1 in the SN achieved by adeno-associated virus-mediated overexpression of Nox1-specific shRNA largely attenuated the actMMP3-mediated dopaminergic neuronal loss. Furthermore, Nox1 expression was significantly attenuated in Mmp3 null mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Together we established novel molecular mechanisms underlying oxidative stress-mediated dopaminergic neuronal death in which MMP3 activation is a key upstream event that leads to mitochondrial ROS, Nox1 induction and eventual dopaminergic neuronal death. Our findings may lead to the development of novel therapeutic approach.
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影响因子：
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通讯作者：
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